The invention relates to a process for carrying out metathesis reactions, the process being carried out continuously and using a ruthenium-containing catalyst.
A fundamental problem of macrocyclisation by ring-closing metathesis reaction (RCM) is presented by the high dilutions required and the resulting large reactor volumes. When an active substance is manufactured on a multi-tonne scale, the large reactor volumes incur major technical expenditure. There is also the danger that, with a limited reactor capacity, there will be logjams caused by insufficient capacity.
The aim of the present invention was to provide a process for carrying out metathesis reactions, particularly macrocyclisations by ring-closing metathesis (RCM), with which these disadvantages can be overcome.
It has now surprisingly been found that carrying out metathesis reactions continuously as opposed to the conventional batch method has the advantage that when they run permanently they require comparatively small reactors, thereby reducing the technical costs. Moreover, a stable continuous process should lead to fewer fluctuations in the quality of the product. The relatively small amounts of solvent contained in the system at any one time further reduce the risks incurred by the handling of highly flammable solvents.
Examples of continuously operating systems with the possibility of ethylene removal are:
Stirred Vessel Cascade (FIG. 1)
A stirred vessel cascade is an in-series arrangement of conventional stirred vessels, in which the reaction solutions spend part of the total retention time or total reaction time in the first vessel, another part in the second etc. The solution is transferred from one vessel to the next by means of pumps or an overflow or the like. At the same time the catalyst solution may be distributed between the various vessels. Efficient elimination of ethylene is ensured by passing a counter-current of nitrogen into the different vessels. The retention time in the individual vessels is preferably such as to achieve maximum yield with as few by-products as possible. The yield of a reaction correlates with the retention time inter alia; for example, at high concentrations of catalyst, the retention time is reduced with the same yield. Conversely, a lower concentration of catalyst requires a longer retention time to achieve the same yield. At identical catalyst concentrations, the more active the catalyst, the lower the retention time required. An example of a stirred vessel cascade is shown in FIG. 1, with the numerals in the figure identifying the following: 1=educt solution, 2=catalyst solution, 3=quench, 4=product solution, 5=nitrogen, 6=exhaust, 7=reaction apparatus 1, 8=reaction apparatus 2, 9=reactor for inactivating the catalyst, 10=transfer pipes.
Packed Column with Introduction of N2 (FIG. 2)
This is a column with a mixer or T-connection provided upstream of it, which is filled with an inert material and is charged with one or more solvent mixtures containing educts and any catalysts. The retention time in the packed column when substrate is in contact with the catalyst is determined by the volume of the packed column and the overall flow rate. The overall flow rate being the total of the individual flow rates selected for the method of delivery used, such as e.g. pumps or gravity-based systems.
The yield of a reaction correlates with the retention time inter alia; for example, at high concentrations of catalyst, the retention time is reduced with the same yield. Conversely, a lower concentration of catalyst requires a longer retention time to achieve the same yield. At identical catalyst concentrations, the more active the catalyst, the lower the retention time required. An example of a packed column is shown in FIG. 2, with the numerals in the figure identifying the following: 1=educt solution, 2=catalyst solution, 3=quench, 4=product solution, 5=nitrogen, 6=exhaust, 7=reaction column, 8=reactor for inactivating the catalyst, 9=transfer pipe.
Falling-Film Reactor or Short-Path Distillation (FIG. 3)
Falling-film apparatus works on the principle that a thin film of liquid flows down the inside of a vertical tube under the effect of gravity. Heat is supplied to the falling film to heat up and/or partially evaporate the liquid. In short-path distillation, for example, the heating medium used is a heat carrier oil which is passed through a double jacket around the outside of the tube. The solution fed in from above is distributed over the temperature-controlled surface by means of a wiper device. The film thickness is dependent not only on substance-specific properties such as density and viscosity but also on throughput. The average retention time is determined from the product of the film thickness and surface area divided by the throughput.
In this particular application short-path distillation would be suitable for better removing the unwanted ethylene released during the reaction more satisfactorily than would be possible using a standard batch method. The thin film produced over a relatively large surface area enables an easier phase change of the ethylene, which can then be carried out of the reaction chamber with a continuous current of nitrogen. An example of a falling-film reactor is shown in FIG. 3, with the numerals in the figure identifying the following: 1=educt solution, 2=catalyst solution, 3=quench, 4=product solution, 5=nitrogen, 6=exhaust, 7=transfer pipe, 8=falling film reactor, 9=reactor for inactivating the catalyst.
Microreactor with Retention Loop (FIG. 4)
The microreactor shown is a static mixer (IMM Interdigital Mixer), into which the fluids to be mixed are fed by means of pumps. Attached to the outlet of the mixer is a retention loop, the retention time being determined by a) the volume of the mixer and the length of the retention path and b) the overall flow rate, which is calculated by adding together the individual flow rates selected for the pumps. If the length of the retention path remains constant, the retention time is very easily varied by changing the pumping rates. The overall set-up can be kept at the desired reaction temperature in a temperature control bath by means of a thermostat. An example of a microreactor with retention loop is shown in FIG. 4, with the numerals in the figure identifying the following: 1=educt solution, 2=catalyst solution, 3=microreactor (reaction), 4=retention loop, 5=thermostatically controlled bath, 6=quench, 7=reactor for inactivating the catalyst, 8=product solution.